Dose optimization for MORAb-202, an antibody-drug conjugate (ADC) highly selective for folate receptor-alpha (FRα), using population pharmacokinetic (PPK) and exposure-response (E-R) efficacy and safety analyses.
Authors: Seiichi Hayato, Lora Hamuro, Maiko Nomoto, Shin Nishio, Kan Yonemori, Mayu Yunokawa, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Yasuyuki Hirashima, Hidenori Kato, Toshio Shimizu, Hiroki Ikezawa, Yohei Otake, Takuma Miura, Yue Zhao, Li Zhu, Trixia Camacho, Calin Dan Dumitru, Sanae Yasuda
Journal: Journal of Clinical Oncology (2022)

3090 Background: MORAb-202 is an ADC consisting of farletuzumab (an antibody that binds to FRα) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin B-cleavable linker. A phase 1 dose-escalation and expansion study in patients with advanced solid tumors evaluated MORAb-202 doses ranging from 0.3 mg/kg to 1.2 mg/kg IV every 3 weeks (Shimizu 2021, CCR). The dose-expansion part included starting doses of 0.9 mg/kg and 1.2 mg/kg in an ovarian cancer (OC) cohort. Objective response rates (ORR) by investigator per RECIST v1.1 and rates of all-grade interstitial lung disease (ILD), an adverse event of interest, were lower at the 0.9 mg/kg dose vs the 1.2 mg/kg dose. To support dose optimization for clinical benefit while reducing the risk of ILD, a MORAb-202 PPK model was developed to characterize the pharmacokinetics and to obtain model-predicted exposure measures. Methods: Exposure was predicted for different dosing scenarios: flat dosing, bodyweight (BW)-based dosing with or without a dose cap, adjusted ideal BW dosing, and body surface area (BSA)-based dosing. E-R analyses for efficacy (ie, ORR) and safety (ie, ILD by expert review) were conducted using logistic-regression analysis. Simulations (N = 1000) were performed using a BW distribution from a previous phase 3 farletuzumab study in OC (Vergote 2016, JCO) to predict the probability of ORR and ILD in patients treated with MORAb-202. Results: MORAb-202 exposures were dose proportional, and the pharmacokinetics were described by a 2-compartment model with zero-order IV infusion and first-order elimination. Patients with higher BW had less-than-proportional increases in clearance (allometric exponent [AE] 0.571) and distribution volume (AE 0.524). MORAb-202 demonstrated a positive exposure (based on area under the curve [AUC]) dependence to ORR and ILD. The probability of achieving a tumor response was higher with higher AUC (odds ratio [OR] for an AUC unit change of 1000 µg•h/mL: 1.73 [95% CI 1.06–3.11]). The probability of an ILD event was higher with higher AUC (OR for an AUC unit change of 1000 µg•h/mL: 3.50 [95% CI 1.89–7.81]). Simulations across BW ranges (34.2–144 kg) indicated that BSA-based dosing (33 mg/m 2 ), compared with BW-based dosing (0.9 mg/kg), yielded similar predicted median (90% prediction interval) rates for ORR (33.7% [19.3–62.2] vs 37.9% [20.6–67.5]) and all-grade ILD (46.8% [18.2–88.2] vs 55.1% [20.7–91.9]). However, BSA-based dosing is predicted to reduce ILD in the highest BW quartile (&gt; 80–144 kg) by approximately 35% compared with BW-based dosing. Conclusions: Based on this assessment, BSA-based dosing is predicted to lower the exposure-dependent ILD risk in patients with higher BW and is being further evaluated in ongoing clinical studies. Clinical trial information: NCT03386942.